Major depressive disorder (MDD) is clearly associated with excess medical morbidity and mortality, including elevated rates of diseases that increase in prevalence with aging such as cardiovascular disease and possibly some cancers. This elevated risk remains even after accounting for differences in health related behaviors such as smoking and exercise, yet little is known about the biological mechanisms underlying this enhanced risk. However, substantial evidence supports abnormalities in stress related biological systems in MDD. Stress response mediators, while adaptive in the short-term, can result in chronic "wear and tear" to tissues and organs in the face of chronic stress responses. We hypothesize those chronic MDD results in abnormalities in stress response systems including a failure to halt acute inflammatory processes that ultimately accelerate aging. Consistent with this hypothesis and recent data showing telomere shortening with psychosocial stress, our two pilot studies demonstrated 1) significantly shorter telomere lengths in individuals with mood disorders, representing as much as 10 years of accelerated aging, and 2) significant elevations in inflammatory cytokines in those with MDD compared to matched controls. Building on recent advances in basic telomere biology and the elucidation of mechanisms underlying oxidative stress, our proposal offers a unique opportunity to translate findings from the laboratory to understanding the detrimental impact of MDD. The primary aim of this study is to examine the impact of chronic MDD as a stress related disorder on measures of accelerated aging. Specifically, DNA damage and telomere shortening, measures of chronic oxidative stress and increased cellular turnover, will be assessed in a clinically well-characterized group of 200 individuals with at least 5 years of MDD and compared to a non-psychiatrically ill age and gender matched control group. In addition, specific proinflammatory cytokines, a marker of organismal inflammation, will be examined as a potential mediator of the effect of MDD on telomere shortening and DNA damage. Detailed clinical and environmental factors will be assessed as potential moderators of the depression- accelerated aging effect. A subsample of 125 individuals with MDD and 125 matched controls will also be longitudinally followed and assessed for prospective change in these measures 2 years later. This study will advance our understanding of the impact of MDD on the development of telomere shortening and DNA damage, culminating in acceleration of aging. This work will elucidate a novel potential mechanistic pathway linking MDD and chronic stress to excess morbidity and mortality, and may reveal important possibilities for therapeutic intervention and prevention of stress related diseases of aging for individuals with MDD. [unreadable] [unreadable] [unreadable]